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Publication
Journal: British Medical Journal
July/21/2004
Abstract
OBJECTIVE
To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital.
METHODS
Prospective observational study.
METHODS
Two large general hospitals in Merseyside, England.
METHODS
18 820 patients aged>> 16 years admitted over six months and assessed for cause of admission.
METHODS
Prevalence of admissions due to an ADR, length of stay, avoidability, and outcome.
RESULTS
There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is 466m pounds sterling (706m Euros, 847m dollars). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding.
CONCLUSIONS
The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.
Publication
Journal: Gut
June/25/2007
Abstract
BACKGROUND
Guidelines on the management of Helicobacter pylori, which cover indications for management and treatment strategies, were produced in 2000.
OBJECTIVE
To update the guidelines at the European Helicobacter Study Group (EHSG) Third Maastricht Consensus Conference, with emphasis on the potential of H pylori eradication for the prevention of gastric cancer.
RESULTS
Eradication of H pylori infection is recommended in (a) patients with gastroduodenal diseases such as peptic ulcer disease and low grade gastric, mucosa associated lymphoid tissue (MALT) lymphoma; (b) patients with atrophic gastritis; (c) first degree relatives of patients with gastric cancer; (d) patients with unexplained iron deficiency anaemia; and (e) patients with chronic idiopathic thrombocytopenic purpura. Recurrent abdominal pain in children is not an indication for a "test and treat" strategy if other causes are excluded. Eradication of H pylori infection (a) does not cause gastro-oesophageal reflux disease (GORD) or exacerbate GORD, and (b) may prevent peptic ulcer in patients who are naïve users of non-steroidal anti-inflammatory drugs (NSAIDs). H pylori eradication is less effective than proton pump inhibitor (PPI) treatment in preventing ulcer recurrence in long term NSAID users. In primary care a test and treat strategy using a non-invasive test is recommended in adult patients with persistent dyspepsia under the age of 45. The urea breath test, stool antigen tests, and serological kits with a high accuracy are non-invasive tests which should be used for the diagnosis of H pylori infection. Triple therapy using a PPI with clarithromycin and amoxicillin or metronidazole given twice daily remains the recommended first choice treatment. Bismuth-containing quadruple therapy, if available, is also a first choice treatment option. Rescue treatment should be based on antimicrobial susceptibility.
CONCLUSIONS
The global burden of gastric cancer is considerable but varies geographically. Eradication of H pylori infection has the potential to reduce the risk of gastric cancer development.
Publication
Journal: British Medical Journal
June/13/2006
Abstract
OBJECTIVE
To assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events.
METHODS
Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs.
METHODS
Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck.
METHODS
Eligible studies were randomised trials that included a comparison of a selective COX 2 inhibitor versus placebo or a selective COX 2 inhibitor versus a traditional NSAID, of at least four weeks' duration, with information on serious vascular events (defined as myocardial infarction, stroke, or vascular death). Individual investigators and manufacturers provided information on the number of patients randomised, numbers of vascular events, and the person time of follow-up for each randomised group.
RESULTS
In placebo comparisons, allocation to a selective COX 2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year v 0.9%/year; rate ratio 1.42, 95% confidence interval 1.13 to 1.78; P = 0.003), with no significant heterogeneity among the different selective COX 2 inhibitors. This was chiefly attributable to an increased risk of myocardial infarction (0.6%/year v 0.3%/year; 1.86, 1.33 to 2.59; P = 0.0003), with little apparent difference in other vascular outcomes. Among trials of at least one year's duration (mean 2.7 years), the rate ratio for vascular events was 1.45 (1.12 to 1.89; P = 0.005). Overall, the incidence of serious vascular events was similar between a selective COX 2 inhibitor and any traditional NSAID (1.0%/year v 0.9%/year; 1.16, 0.97 to 1.38; P = 0.1). However, statistical heterogeneity (P = 0.001) was found between trials of a selective COX 2 inhibitor versus naproxen (1.57, 1.21 to 2.03) and of a selective COX 2 inhibitor versus non-naproxen NSAIDs (0.88, 0.69 to 1.12). The summary rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac.
CONCLUSIONS
Selective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.
Publication
Journal: Cell
November/22/1999
Abstract
PPARB was identified as a target of APC through the analysis of global gene expression profiles in human colorectal cancer (CRC) cells. PPARdelta expression was elevated in CRCs and repressed by APC in CRC cells. This repression was mediated by beta-catenin/Tcf-4-responsive elements in the PPARdelta promotor. The ability of PPARs to bind eicosanoids suggested that PPARdelta might be a target of chemopreventive non-steroidal anti-inflammatory drugs (NSAIDs). Reporters containing PPARdelta-responsive elements were repressed by the NSAID sulindac. Furthermore, sulindac was able to disrupt the ability of PPARdelta to bind its recognition sequences. These findings suggest that NSAIDs inhibit tumorigenesis through inhibition of PPARdelta, the gene for which is normally regulated by APC.
Publication
Journal: Annals of the Rheumatic Diseases
November/27/2006
Abstract
OBJECTIVE
To develop evidence based recommendations for the management of gout.
METHODS
The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert representing 13 European countries. Key propositions on management were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Where possible, effect size (ES), number needed to treat, relative risk, odds ratio, and incremental cost-effectiveness ratio were calculated. The quality of evidence was categorised according to the level of evidence. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales.
RESULTS
12 key propositions were generated after three Delphi rounds. Propositions included both non-pharmacological and pharmacological treatments and addressed symptomatic control of acute gout, urate lowering therapy (ULT), and prophylaxis of acute attacks. The importance of patient education, modification of adverse lifestyle (weight loss if obese; reduced alcohol consumption; low animal purine diet) and treatment of associated comorbidity and risk factors were emphasised. Recommended drugs for acute attacks were oral non-steroidal anti-inflammatory drugs (NSAIDs), oral colchicine (ES = 0.87 (95% confidence interval, 0.25 to 1.50)), or joint aspiration and injection of corticosteroid. ULT is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. Allopurinol was confirmed as effective long term ULT (ES = 1.39 (0.78 to 2.01)). If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, allopurinol desensitisation, or a uricosuric. The uricosuric benzbromarone is more effective than allopurinol (ES = 1.50 (0.76 to 2.24)) and can be used in patients with mild to moderate renal insufficiency but may be hepatotoxic. When gout is associated with the use of diuretics, the diuretic should be stopped if possible. For prophylaxis against acute attacks, either colchicine 0.5-1 mg daily or an NSAID (with gastroprotection if indicated) are recommended.
CONCLUSIONS
12 key recommendations for management of gout were developed, using a combination of research based evidence and expert consensus. The evidence was evaluated and the SOR provided for each proposition.
Publication
Journal: Gut
August/11/1996
Abstract
The aim of this study was to establish the relative importance of risk factors for mortality after acute upper gastrointestinal haemorrhage, and to formulate a simple numerical scoring system that categorizes patients by risk. A prospective, unselected, multicentre, population based study was undertaken using standardised questionnaires in two phases one year apart. A total of 4185 cases of acute upper gastrointestinal haemorrhage over the age of 16 identified over a four month period in 1993 and 1625 cases identified subsequently over a three month period in 1994 were included in the study. It was found that age, shock, comorbidity, diagnosis, major stigmata of recent haemorrhage, and rebleeding are all independent predictors of mortality when assessed using multiple logistic regression. A numerical score using these parameters has been developed that closely follows the predictions generated by logistical regression equations. Haemoglobin, sex, presentation (other than shock), and drug therapy (non-steroidal anti-inflammatory drugs and anticoagulants) are not represented in the final model. When tested for general applicability in a second population, the scoring system was found to reproducibly predict mortality in each risk category. In conclusion, a simple numerical score can be used to categorize patients presenting with acute upper gastrointestinal haemorrhage by risk of death. This score can be used to determine case mix when comparing outcomes in audit and research and to calculate risk standardised mortality. In addition, this risk score can identify 15% of all cases with acute upper gastrointestinal haemorrhage at the time of presentation and 26% of cases after endoscopy who are at low risk of rebleeding and negligible risk of death and who might therefore be considered for early discharge or outpatient treatment with consequent resource savings.
Publication
Journal: Gut
January/17/2006
Abstract
Chemoprevention has been considered as a possible approach for cancer prevention. A significant effort has been made in the development of novel drugs for both cancer prevention and treatment over the past decade. Recent epidemiological studies and clinical trials indicate that long term use of aspirin and similar agents, also called non-steroidal anti-inflammatory drugs (NSAIDs), can decrease the incidence of certain malignancies, including colorectal, oesophageal, breast, lung, and bladder cancers. The best known targets of NSAIDs are cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins (PGs) and thromboxane. COX-2 derived prostaglandin E(2)(PGE(2)) can promote tumour growth by binding its receptors and activating signalling pathways which control cell proliferation, migration, apoptosis, and/or angiogenesis. However, the prolonged use of high dosages of COX-2 selective inhibitors (COXIBs) is associated with unacceptable cardiovascular side effects. Thus it is crucial to develop more effective chemopreventive agents with minimal toxicity. Recent efforts to identify the molecular mechanisms by which PGE(2) promotes tumour growth and metastasis may provide opportunities for the development of safer strategies for cancer prevention and treatment.
Publication
Journal: BMJ (Clinical research ed.)
June/4/1991
Abstract
OBJECTIVE
To determine the extent of agreement between clinical information recorded on surgery computers of selected general practitioners and similar information in manual records of letters received from hospital consultants and kept in the general practitioners' files.
METHODS
Hospital consultants' letters in the manual records of selected general practitioners were photocopied and the consultants' clinical diagnoses were compared with diagnoses recorded on computer.
METHODS
General practices in the United Kingdom using computers provided by VAMP Health for recording clinical information.
METHODS
2491 patients who received one of three non-steroidal anti-inflammatory drugs and who attended 58 practices whose computer recorded data were considered after a preliminary review to be of satisfactory quality.
RESULTS
Among 1191 patients for whom consultants' letters were forwarded a clinical diagnosis reflecting the diagnosis noted on a consultant letter was present on the computer record for 1038 (87%).
CONCLUSIONS
Clinical information available on the computer records of the general practitioners who participated in this study is satisfactory for many clinical studies.
Publication
Journal: Annals of the Rheumatic Diseases
April/19/2006
Abstract
OBJECTIVE
To develop evidence based recommendations for the management of ankylosing spondylitis (AS) as a combined effort of the 'ASsessment in AS' international working group and the European League Against Rheumatism.
METHODS
Each of the 22 participants was asked to contribute up to 15 propositions describing key clinical aspects of AS management. A Delphi process was used to select 10 final propositions. A systematic literature search was then performed to obtain scientific evidence for each proposition. Outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, relative risk, number needed to treat, and incremental cost effectiveness ratio were calculated. On the basis of the search results, 10 major recommendations for the management of AS were constructed. The strength of recommendation was assessed based on the strength of the literature evidence, risk-benefit trade-off, and clinical expertise.
RESULTS
The final recommendations considered the use of non-steroidal anti-inflammatory drugs (NSAIDs) (conventional NSAIDs, coxibs, and co-prescription of gastroprotective agents), disease modifying antirheumatic drugs, treatments with biological agents, simple analgesics, local and systemic steroids, non-pharmacological treatment (including education, exercise, and physiotherapy), and surgical interventions. Three general recommendations were also included. Research evidence (categories I-IV) supported 11 interventions in the treatment of AS. Strength of recommendation varied, depending on the category of evidence and expert opinion.
CONCLUSIONS
Ten key recommendations for the treatment of AS were developed and assessed using a combination of research based evidence and expert consensus. Regular updating will be carried out to keep abreast of new developments in the management of AS.
Publication
Journal: BMJ (Clinical research ed.)
August/4/1996
Abstract
OBJECTIVE
To compare the relative risks of serious gastrointestinal complications reported with individual non-steroidal anti-inflammatory drugs.
METHODS
Systematic review of controlled epidemiological studies that found a relation between use of the drugs and admission to hospital for haemorrhage or perforation.
METHODS
Hospital and community based case-control and cohort studies.
METHODS
(a) Estimated relative risks of gastrointestinal complications with use of individual drugs, exposure to ibuprofen being used as reference; (b) a ranking that best summarised the sequence of relative risks observed in the studies.
RESULTS
12 studies met the inclusion criteria. 11 provided comparative data on ibuprofen and other drugs. Ibuprofen ranked lowest or equal lowest for risk in 10 of the 11 studies. Pooled relative risks calculated with exposure to ibuprofen used as reference were all significantly greater than 1.0 (interval of point estimates 1.6 to 9.2). Overall, ibuprofen was associated with the lowest relative risk, followed by diclofenac. Azapropazone, tolmetin, ketoprofen, and piroxicam ranked highest for risk and indomethacin, naproxen, sulindac, and aspirin occupied intermediate positions. Higher doses of ibuprofen were associated with relative risks similar to those with naproxen and indomethacin.
CONCLUSIONS
The low risk of serious gastrointestinal complications with ibuprofen seems to be attributable mainly to the low doses of the drug used in clinical practice. In higher doses ibuprofen is associated with a similar risk to other non-steroidal anti-inflammatory drugs. Use of low risk drugs in low dosage as first line treatment would substantially reduce the morbidity and mortality due to serious gastrointestinal toxicity from these drugs.
Publication
Journal: Annals of the Rheumatic Diseases
May/30/2020
Abstract
Objectives: COVID-19 outcomes in people with rheumatic diseases remain poorly understood. The aim was to examine demographic and clinical factors associated with COVID-19 hospitalisation status in people with rheumatic disease.
Methods: Case series of individuals with rheumatic disease and COVID-19 from the COVID-19 Global Rheumatology Alliance registry: 24 March 2020 to 20 April 2020. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities and rheumatic disease medications taken immediately prior to infection were analysed.
Results: A total of 600 cases from 40 countries were included. Nearly half of the cases were hospitalised (277, 46%) and 55 (9%) died. In multivariable-adjusted models, prednisone dose ≥10 mg/day was associated with higher odds of hospitalisation (OR 2.05, 95% CI 1.06 to 3.96). Use of conventional disease-modifying antirheumatic drug (DMARD) alone or in combination with biologics/Janus Kinase inhibitors was not associated with hospitalisation (OR 1.23, 95% CI 0.70 to 2.17 and OR 0.74, 95% CI 0.37 to 1.46, respectively). Non-steroidal anti-inflammatory drug (NSAID) use was not associated with hospitalisation status (OR 0.64, 95% CI 0.39 to 1.06). Tumour necrosis factor inhibitor (anti-TNF) use was associated with a reduced odds of hospitalisation (OR 0.40, 95% CI 0.19 to 0.81), while no association with antimalarial use (OR 0.94, 95% CI 0.57 to 1.57) was observed.
Conclusions: We found that glucocorticoid exposure of ≥10 mg/day is associated with a higher odds of hospitalisation and anti-TNF with a decreased odds of hospitalisation in patients with rheumatic disease. Neither exposure to DMARDs nor NSAIDs were associated with increased odds of hospitalisation.
Keywords: arthritis, rheumatoid; hydroxychloroquine; lupus erythematosus, systemic; methotrexate; tumor necrosis factor inhibitors.
Publication
Journal: Gut
August/17/1987
Abstract
Two hundred and thirty five consecutive patients with a life threatening complication of peptic ulceration, who either died or required emergency surgery, have been studied over a 36 month period. Seventy eight of these high risk patients died; 25 at home, 19 in hospital without surgery and 34 postoperatively. Ninety eight patients had bleeding ulcers, 132 perforated ulcers and five had both bleeding and perforated ulcers. One hundred and forty one of these 235 patients (60%) were taking a non-steroidal anti-inflammatory drugs (NSAID) and the individual agents have been listed. The overall incidence of NSAID use in a hospital control group was 9.9%. The first sign of an ulcer was a life threatening complication in 58.2% of patients taking a NSAID. Nearly 80% of all ulcer related deaths occurred in patients using an anti-inflammatory agent. Patients using these drugs were older, with more pre-existing medical conditions and had larger ulcers than those not taking NSAIDs. The mortality associated with a peptic ulcer complication in patients taking a NSAID was more than twice that in patients with no such drug history. There appears to be a relationship between the development of a life threatening complication of peptic ulceration and NSAID ingestion. Much of the associated mortality and morbidity may be potentially avoidable.
Publication
Journal: British Medical Journal
June/26/2005
Abstract
OBJECTIVE
To determine the comparative risk of myocardial infarction in patients taking cyclo-oxygenase-2 and other non-steroidal anti-inflammatory drugs (NSAIDs) in primary care between 2000 and 2004; to determine these risks in patients with and without pre-existing coronary heart disease and in those taking and not taking aspirin.
METHODS
Nested case-control study.
METHODS
367 general practices contributing to the UK QRESEARCH database and spread throughout every strategic health authority and health board in England, Wales, and Scotland.
METHODS
9218 cases with a first ever diagnosis of myocardial infarction during the four year study period; 86 349 controls matched for age, calendar year, sex, and practice.
METHODS
Unadjusted and adjusted odds ratios with 95% confidence intervals for myocardial infarction associated with rofecoxib, celecoxib, naproxen, ibuprofen, diclofenac, and other selective and non-selective NSAIDS. Odds ratios were adjusted for smoking status, comorbidity, deprivation, and use of statins, aspirin, and antidepressants.
RESULTS
A significantly increased risk of myocardial infarction was associated with current use of rofecoxib (adjusted odds ratio 1.32, 95% confidence interval 1.09 to 1.61) compared with no use within the previous three years; with current use of diclofenac (1.55, 1.39 to 1.72); and with current use of ibuprofen (1.24, 1.11 to 1.39). Increased risks were associated with the other selective NSAIDs, with naproxen, and with non-selective NSAIDs; these risks were significant at < 0.05 rather than < 0.01 for current use but significant at < 0.01 in the tests for trend. No significant interactions occurred between any of the NSAIDs and either aspirin or coronary heart disease.
CONCLUSIONS
These results suggest an increased risk of myocardial infarction associated with current use of rofecoxib, diclofenac, and ibuprofen despite adjustment for many potential confounders. No evidence was found to support a reduction in risk of myocardial infarction associated with current use of naproxen. This is an observational study and may be subject to residual confounding that cannot be fully corrected for. However, enough concerns may exist to warrant a reconsideration of the cardiovascular safety of all NSAIDs.
Publication
Journal: Annals of the Rheumatic Diseases
December/30/2002
Abstract
Ankylosing spondylitis (AS) is a complex, potentially debilitating disease that is insidious in onset, progressing to radiological sacroiliitis over several years. Patients with symptomatic AS lose productivity owing to work disability and unemployment, have a substantial use of healthcare resources, and reduced quality of life. The pathogenesis of AS is poorly understood. However, immune mediated mechanisms involving human leucocyte antigen (HLA)-B27, inflammatory cellular infiltrates, cytokines (for example, tumour necrosis factor alpha and interleukin 10), and genetic and environmental factors are thought to have key roles. The detection of sacroiliitis by radiography, magnetic resonance imaging, or computed tomography in the presence of clinical manifestations is diagnostic for AS, although the presence of inflammatory back pain plus at least two other typical features of spondyloarthropathy (for example, enthesitis and uveitis) is highly predictive of early AS. Non-steroidal anti-inflammatory drugs (NSAIDs) effectively relieve inflammatory symptoms and are presently first line drug treatment. However, NSAID treatment has only a symptomatic effect and probably does not alter the disease course. For symptoms refractory to NSAIDs, second line treatments, including corticosteroids and various disease modifying antirheumatic drugs, are employed but are of limited benefit. Emerging biological therapies target the inflammatory processes underlying AS, and thus, may favourably alter the disease process, in addition to providing symptom relief.
Publication
Journal: Annals of the Rheumatic Diseases
February/23/2005
Abstract
OBJECTIVE
To examine the epidemiology of gout and gout treatment in the United Kingdom using a large national practice based population.
METHODS
Data from the UK General Practice Research Database from 1990 to 1999 were examined. Physician diagnoses and drug codes were used, and trends in gout incidence and treatment examined. Additionally, disease prevalence for the year 1999 was assessed. To examine the association of gout with comorbid disease, the prevalence of select health conditions and drug use was compared with the corresponding prevalences seen in osteoarthritis, adjusting for both age and sex.
RESULTS
From 1 January 1990 to 31 December 1999 overall gout incidence remained relatively stable, ranging from a low of 11.9 cases (95% confidence interval (CI) 11.5 to 12.3) in 1991 to a high of 18.0 cases (95% CI 17.6 to 18.4) per 10 000 patient-years in 1994. Gout prevalence in 1999 was 1.4% with rates approaching 7% in men over the age of 65. Drugs used for the treatment of gout remained constant in prevalent cases with the exception of a significant decline in non-steroidal anti-inflammatory drug use over the 10 year follow up. Compared with patients with osteoarthritis, patients with gout were significantly more likely to have cardiovascular disease, hypertension, diabetes, and chronic renal failure, and were more likely to have used diuretics or ciclosporin, or both.
CONCLUSIONS
Although gout is common in the UK, particularly among older men, the incidence of the disease seems to have remained stable during the 1990s.
Publication
Journal: British Medical Journal
July/27/2003
Abstract
OBJECTIVE
To quantify the risk of Alzheimer's disease in users of all non-steroidal anti-inflammatory drugs (NSAIDs) and users of aspirin and to determine any influence of duration of use.
METHODS
Systematic review and meta-analysis of observational studies published between 1966 and October 2002 that examined the role of NSAID use in preventing Alzheimer's disease. Studies identified through Medline, Embase, International Pharmaceutical Abstracts, and the Cochrane Library.
RESULTS
Nine studies looked at all NSAIDs in adults aged>> 55 years. Six were cohort studies (total of 13 211 participants), and three were case-control studies (1443 participants). The pooled relative risk of Alzheimer's disease among users of NSAIDs was 0.72 (95% confidence interval 0.56 to 0.94). The risk was 0.95 (0.70 to 1.29) among short term users (< 1 month) and 0.83 (0.65 to 1.06) and 0.27 (0.13 to 0.58) among intermediate term (mostly < 24 months) and long term (mostly>> 24 months) users, respectively. The pooled relative risk in the eight studies of aspirin users was 0.87 (0.70 to 1.07).
CONCLUSIONS
NSAIDs offer some protection against the development of Alzheimer's disease. The appropriate dosage and duration of drug use and the ratios of risk to benefit are still unclear.
Publication
Journal: Nature
July/17/2008
Abstract
Selective lowering of Abeta42 levels (the 42-residue isoform of the amyloid-beta peptide) with small-molecule gamma-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the gamma-secretase complex, but instead labelled the beta-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-beta peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP gamma-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28-36 of amyloid-beta, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-beta act as GSMs, and some GSMs alter the production of cell-derived amyloid-beta oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in Abeta42 production and inhibition of amyloid-beta aggregation, which may synergistically reduce amyloid-beta deposition in Alzheimer's disease. These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets.